Suicidality And Antidepressant Drugs

Antidepressants increased the risk of suicidal
thoughts and behavior in children, adolescents, and young adults in short-term
trials. These trials did not show an increase in the risk of suicidal thoughts
and behavior with antidepressant use in subjects over age 24; there was a
reduction in risk with antidepressant use in subjects aged 65 and older [see WARNINGS
AND PRECAUTIONS].

In patients of all ages who are started on
antidepressant therapy, monitor closely for worsening, and for emergence of
suicidal thoughts and behaviors . Advise families and caregivers of the need
for close observation and communication with the prescriber [see WARNINGS AND
PRECAUTIONS].

Serious neuropsychiatric reactions have occurred in
patients taking bupropion for smoking cessation [see WARNINGS AND
PRECAUTIONS].
The majority of these reactions occurred during bupropion treatment, but some
occurred in the context of discontinuing treatment. In many cases, a causal
relations hip to bupropion treatment is not certain, because depressed mood may
be a symptom of nicotine withdrawal. However, some of the cases occurred in
patients taking bupropion who continued to smoke. Although WELLBUTRIN®
SR is not approved for smoking cessation, observe all patients for
neuropsychiatric reactions. Instruct the patient to contact a healthcare provider
if such reactions occur [see WARNINGS AND
PRECAUTIONS].

DESCRIPTION

WELLBUTRIN SR (bupropion hydrochloride), an
antidepressant of the aminoketone class, is chemically unrelated to tricyclic,
tetracyclic, selective serotoninre-uptake
inhibitor, or other known antidepressant agents. Its structure closely
resembles that of diethylpropion; it is related to phenylethylamines. It is
designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride.
The molecular weight is 276.2. The molecular formula is C13H18ClNO•HCl.
Bupropion hydrochloride powder is white, crystalline, and highly soluble in
water. It has a bitter taste and produces the sensation of local anesthesia on
the oral mucosa. The structural formula is:

INDICATIONS

WELLBUTRIN SR (bupropion hydrochloride) is indicated for
the treatment of major depressive disorder (MDD), as defined by the Diagnostic
and Statistical Manual (DSM).

The efficacy of bupropion in the treatment of a major
depressive episode was established in two 4- week controlled inpatient trials
and one 6-week controlled outpatient trial of adult subjects with MDD [see Clinical
Studies].

DOSAGE AND ADMINISTRATION

General Instructions For Use

To minimize the risk of seizure, increase the dose
gradually [see WARNINGS AND PRECAUTIONS]. WELLBUTRIN SR tablets should
be swallowed whole and not crushed, divided, or chewed. WELLBUTRIN SR may be
taken with or without food.

The usual adult target dose for WELLBUTRIN SR is 300 mg
per day, given as 150 mg twice daily. Initiate dosing with 150 mg per day given
as a single daily dose in the morning. After 3 days of dosing, the dose may be
increased to the 300-mg-per-day target dose, given as 150 mg twice daily. There
should be an interval of at least 8 hours between successive doses. A maximum
of 400 mg per day, given as 200 mg twice daily, may be considered for patients
in whom no clinical improvement is noted after several weeks of treatment at
300 mg per day. To avoid high peak concentrations of bupropion and/or its
metabolites, do not exceed 200 mg in any single dose.

It is generally agreed that acute episodes of depression
require several months or longer of antidepressant drug treatment beyond the
response in the acute episode. It is unknown whether the dose of WELLBUTRIN SR
needed for maintenance treatment is identical to the dose that provided an
initial response. Periodically reassess the need for maintenance treatment and
the appropriate dose for such treatment.

Dose Adjustment In Patients With Hepatic Impairment

In patients with moderate to severe hepatic impairment
(Child-Pugh score: 7 to 15), the maximum dose of WELLBUTRIN SR is 100 mg per
day or 150 mg every other day. In patients with mild hepatic impairment
(Child-Pugh score: 5 to 6), consider reducing the dose and/or frequency of
dosing [see Use in Specific Populations, CLINICAL PHARMACOLOGY].

Switching A Patient To Or From A Monoamine Oxidase
Inhibitor (MAOI) Antidepressant

At least 14 days should elapse between discontinuation of
an MAOI intended to treat depression and initiation of therapy with WELLBUTRIN
SR. Conversely, at least 14 days should be allowed after stopping WELLBUTRIN SR
before starting an MAOI antidepressant [seeCONTRAINDICATIONS, DRUG
INTERACTIONS].

Use Of WELLBUTRIN SR With Reversible MAOIs Such As Linezolid
Or Methylene Blue

Do not start WELLBUTRIN SR in a patient who is being
treated with a reversible MAOI such as linezolid or intravenous methylene blue.
Drug interactions can increase the risk of hypertensive reactions. In a patient
who requires more urgent treatment of a psychiatric condition,
nonpharmacological interventions, including hospitalization, should be
considered [seeCONTRAINDICATIONS, DRUG INTERACTIONS].

In some cases, a patient already receiving therapy with WELLBUTRIN
SR may require urgent treatment with linezolid or intravenous methylene blue.
If acceptable alternatives to linezolid or intravenous methylene blue treatment
are not available and the potential benefits of linezolid or intravenous methylene
blue treatment are judged to outweigh the risks of hypertensive reactions in a
particular patient, WELLBUTRIN SR should be stopped promptly, and linezolid or
intravenous methylene blue can be administered. The patient should be monitored
for 2 weeks or until 24 hours after the last dose of linezolid or intravenous
methylene blue, whichever comes first. Therapy with WELLBUTRIN SR may be
resumed 24 hours after the last dose of linezolid or intravenous methylene
blue.

The risk of administering methylene blue by non-intravenous
routes (such as oral tablets or by local injection) or in intravenous doses
much lower than 1 mg per kg with WELLBUTRIN SR is unclear. The clinician
should, nevertheless, be aware of the possibility of a drug interaction with
such use [seeCONTRAINDICATIONS, DRUG INTERACTIONS].

Clinical Trials Experience

Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared with rates in the clinical trials of another drug
and may not reflect the rates observed in clinical practice.

Adverse Reactions Leading To Discontinuation Of Treatment

In placebo-controlled
clinical trials, 4%, 9%, and 11% of the placebo, 300-mg-per-day, and 400-mg per-
day groups, respectively, discontinued treatment due to adverse reactions. The
specific adverse reactions leading to discontinuation in at least 1% of the
300-mg-per-day or 400-mg-per-day groups and at a rate at least twice the
placebo rate are listed in Table 2.

Commonly Observed Adverse Reactions

Adverse reactions from Table 3 occurring in at least 5%
of subjects treated with WELLBUTRIN SR and at a rate at least twice the placebo
rate are listed below for the 300- and 400-mg-per-day
dose groups.

Adverse reactions reported in placebo-controlled trials
are presented in Table 3. Reported adverse reactions were classified using a
COSTART-based Dictionary.

Table 3: Adverse Reactions Reported by at Least 1% of
Subjects and at a Greater Frequency than Placebo in Controlled Clinical Trials

Body System/ Adverse Reaction

WELLBUTRIN SR 300 mg/day
(n=376)

WELLBUTRIN SR 400 mg/day
(n = 114)

Placebo
(n = 385)

Body (General)

Headache

26%

25%

23%

Infection

8%

9%

6%

Abdominal pain

3%

9%

2%

Asthenia

2%

4%

2%

Chest pain

3%

4%

1%

Pain

2%

3%

2%

Fever

1%

2%

—

Cardiovascular

Palpitation

2%

6%

2%

Flushing

1%

4%

—

Migraine

1%

4%

1%

Hot flashes

1%

3%

1%

Digestive

Dry mouth

17%

24%

7%

Nausea

13%

18%

8%

Constipation

10%

5%

7%

Diarrhea

5%

7%

6%

Anorexia

5%

3%

2%

Vomiting

4%

2%

2%

Dysphagia

0%

2%

0%

Musculoskeletal

Myalgia

2%

6%

3%

Arthralgia

1%

4%

1%

Arthritis

0%

2%

0%

Twitch

1%

2%

—

Nervous system

Insomnia

11%

16%

6%

Dizziness

7%

11%

5%

Agitation

3%

9%

2%

Anxiety

5%

6%

3%

Tremor

6%

3%

1%

Nervousness

5%

3%

3%

Somnolence

2%

3%

2%

Irritability

3%

2%

2%

Memory decreased

—

3%

1%

Paresthesia

1%

2%

1%

Central nervous system stimulation

2%

1%

1%

Respiratory

Pharyngitis

3%

11%

2%

Sinusitis

3%

1%

2%

Increased cough

1%

2%

1%

Skin

Sweating

6%

5%

2%

Rash

5%

4%

1%

Pruritus

2%

4%

2%

Urticaria

2%

1%

0%

Special senses

Tinnitus

6%

6%

2%

Taste perversion

2%

4%

—

Blurred vision or diplopia

3%

2%

2%

Urogenital

Urinary frequency

2%

5%

2%

Urinary urgency

—

2%

0%

Vaginal hemorrhagea

0%

2%

—

Urinary tract infection

1%

0%

—

aIncidence based on the number of female
subjects.
— Hyphen denotes adverse events occurring in greater than 0 but less than 0.5%
of subjects.

Other Adverse Reactions Observed During The Clinical
Development Of Bupropion

In addition to the adverse reactions noted above, the
following adverse reactions have been reported in clinical trials with the
sustained-release
formulation of bupropion in depressed subjects and in nondepressed smokers, as
well as in clinical trials with the immediate-release
formulation of bupropion.

Adverse reaction frequencies represent the proportion of
subjects who experienced a treatment-emergent
adverse reaction on at least one occasion in placebo-controlled trials for depression (n = 987) or
smoking cessation (n = 1,013), or subjects who experienced an adverse reaction
requiring discontinuation of treatment in an open-label
surveillance trial with WELLBUTRIN SR (n = 3,100). All treatment-emergent adverse reactions are
included except those listed in Table 3, those listed in other safety-related sections of the
prescribing information, those subsumed under COSTART terms that are either
overly general or excessively specific so as to be uninformative, those not
reasonably associated with the use of the drug, and those that were not serious
and occurred in fewer than 2 subjects.

Adverse reactions are further categorized by body system
and listed in order of decreasing frequency according to the following
definitions of frequency: Frequent adverse reactions are defined as those occurring
in at least 1/100 subjects. Infrequent adverse reactions are those occurring in
1/100 to 1/1,000 subjects, while rare events are those occurring in less than
1/1,000 subjects.

In clinical trials conducted with the immediate-release formulation of
bupropion, 35% of subjects receiving tricyclic antidepressants gained weight,
compared with 9% of subjects treated with the immediate-release formulation of bupropion. If weight loss
is a major presenting sign of a patient's depressive illness, the anorectic
and/or weight-reducing
potential of WELLBUTRIN SR should be considered.

Postmarketing Experience

The following adverse reactions have been identified
during post-approval use of WELLBUTRIN SR and are not described elsewhere in
the label. Because these reactions are reported voluntarily from a population
of uncertain size, it is not always possible to reliably estimate their
frequency or establish a causal relationship to drug exposure.

Body (General)

Arthralgia, myalgia, and fever with rash and other
symptoms suggestive of delayed hypersensitivity. These symptoms may resemble
serum sickness [see WARNINGS AND PRECAUTIONS].

DRUG INTERACTIONS

Potential For Other Drugs To Affect WELLBUTRIN SR

Bupropion is primarily metabolized to hydroxybupropion by
CYP2B6. Therefore, the potential exists for drug interactions between
WELLBUTRIN SR and drugs that are inhibitors or inducers of CYP2B6.

Inhibitors Of CYP2B6

Ticlopidine and Clopidogrel: Concomitant treatment with
these drugs can increase bupropion exposure but decrease hydroxybupropion
exposure. Based on clinical response, dosage adjustment of WELLBUTRIN SR may be
necessary when coadministered with CYP2B6 inhibitors (e.g., ticlopidine or
clopidogrel) [see CLINICAL PHARMACOLOGY].

Inducers Of CYP2B6

Ritonavir, Lopinavir, and Efavirenz: Concomitant
treatment with these drugs can decrease bupropion and hydroxybupropion
exposure. Dosage increase of WELLBUTRIN SR may be necessary when coadministered
with ritonavir, lopinavir, or efavirenz [see CLINICAL PHARMACOLOGY] but
should not exceed the maximum recommended dose. Carbamazepine, Phenobarbital,
Phenytoin: While not systematically studied, these drugs may induce the metabolism
of bupropion and may decrease bupropion exposure [see CLINICAL PHARMACOLOGY].
If bupropion is used concomitantly with a CYP inducer, it may be necessary to
increase the dose of bupropion, but the maximum recommended dose should not be
exceeded.

Potential For WELLBUTRIN SR To Affect Other Drugs

Drugs Metabolized By CYP2D6

Bupropion and its metabolites (erythrohydrobupropion,
threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. Therefore, coadministration
of WELLBUTRIN SR with drugs that are metabolized by CYP2D6 can increase the
exposures of drugs that are substrates of CYP2D6. Such drugs include certain
antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine,
paroxetine, fluoxetine, and sertraline), antipsychotics (e.g., haloperidol,
risperidone, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C
antiarrhythmics (e.g., propafenone and flecainide). When used concomitantly with
WELLBUTRIN SR, it may be necessary to decrease the dose of these CYP2D6
substrates, particularly for drugs with a narrow therapeutic index.

Drugs that require metabolic activation by CYP2D6 to be
effective (e.g., tamoxifen) theoretically could have reduced efficacy when
administered concomitantly with inhibitors of CYP2D6 such as bupropion. Patients
treated concomitantly with WELLBUTRIN SR and such drugs may require increased
doses of the drug [seeCLINICAL PHARMACOLOGY].

Dopaminergic Drugs (Levodopa And Amantadine)

Bupropion, levodopa, and amantadine have dopamineagonist
effects. CNS toxicity has been reported when bupropion was coadministered with
levodopa or amantadine. Adverse reactions have included restlessness,
agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness. It is
presumed that the toxicity results from cumulative dopamine agonist effects.
Use caution when administering WELLBUTRIN SR concomitantly with these drugs.

Use With Alcohol

In postmarketing experience, there have been rare reports
of adverse neuropsychiatric events or reduced alcohol tolerance in patients who
were drinking alcohol during treatment with WELLBUTRIN SR. The consumption of
alcohol during treatment with WELLBUTRIN SR should be minimized or avoided.

MAO Inhibitors

Bupropion inhibits the reuptake of dopamine and
norepinephrine. Concomitant use of MAOIs and bupropion is contraindicated
because there is an increased risk of hypertensive reactions if bupropion is
used concomitantly with MAOIs. Studies in animals demonstrate that the acute
toxicity of bupropion is enhanced by the MAO inhibitor phenelzine. At least 14
days should elapse between discontinuation of an MAOI intended to treat
depression and initiation of treatment with WELLBUTRIN SR. Conversely, at least
14 days should be allowed after stopping WELLBUTRIN SR before starting an MAOI antidepressant
[seeDOSAGE AND ADMINISTRATION, CONTRAINDICATIONS].

Drug-Laboratory Test Interactions

False-positive urine immunoassay screening tests for
amphetamines have been reported in patients taking bupropion. This is due to
lack of specificity of some screening tests. False-positive test results may
result even following discontinuation of bupropion therapy. Confirmatory tests,
such as gas chromatography/mass spectrometry, will distinguish bupropion from
amphetamines.

Drug Abuse And Dependence

Controlled Substance

Bupropion is not a controlled substance.

Abuse

Humans

Controlled clinical trials conducted in normal
volunteers, in subjects with a history of multiple drug abuse, and in depressed
subjects showed some increase in motor activity and agitation/excitement, often
typical of central stimulant activity.

In a population of individuals experienced with drugs of
abuse, a single oral dose of 400 mg of bupropion produced mild amphetamine-like activity as compared with
placebo on the Morphine-Benzedrine
Subscale of the Addiction Research Center Inventories (ARCI) and a score greater
than placebo but less than 15 mg of the Schedule II stimulant dextroamphetamine
on the Liking Scale of the ARCI. These scales measure general feelings of
euphoria and drug liking which are often associated with abuse potential.

Findings in clinical trials, however, are not known to
reliably predict the abuse potential of drugs. Nonetheless, evidence from
single-dose trials does
suggest that the recommended daily dosage of bupropion when administered orally
in divided doses is not likely to be significantly reinforcing to amphetamine
or CNS stimulant abusers. However, higher doses (which could not be tested
because of the risk of seizure) might be modestly attractive to those who abuse
CNS stimulant drugs.

WELLBUTRIN SR is intended for oral use only. The
inhalation of crushed tablets or injection of dissolved bupropion has been
reported. Seizures and/or cases of death have been reported when bupropion has
been administered intranasally or by parenteral injection.

Animals

Studies in rodents and primates demonstrated that
bupropion exhibits some pharmacologic actions common to psychostimulants. In
rodents, it has been shown to increase locomotor activity, elicit a mild stereotyped
behavior response, and increase rates of responding in several schedule-controlled behavior paradigms.
In primate models assessing the positive reinforcing effects of psychoactive drugs,
bupropion was self-administered intravenously. In rats, bupropion produced
amphetamine-like and cocaine-like discriminative stimulus effects in drug
discrimination paradigms used to characterize the subjective effects of
psychoactive drugs.

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Suicidal Thoughts And Behaviors In Children, Adoles cents
, and Young Adults

Patients with MDD, both adult and pediatric, may
experience worsening of their depression and/or the emergence of suicidal
ideation and behavior (suicidality) or unusual changes in behavior, whether or not
they are taking antidepressant medications, and this risk may persist until
significant remission occurs. Suicide is a known risk of depression and certain
other psychiatric disorders, and these disorders themselves are the strongest
predictors of suicide. There has been a long-standing concern that
antidepressants may have a role in inducing worsening of depression and the
emergence of suicidality in certain patients during the early phases of
treatment.

Pooled analyses of short-term placebo-controlled trials
of antidepressant drugs (selective serotoninreuptake inhibitors [SSRIs] and
others) show that these drugs increase the risk of suicidal thinking and behavior
(suicidality) in children, adolescents, and young adults (ages 18 to 24) with
MDD and other psychiatric disorders. Short-term clinical trials did not show an
increase in the risk of suicidality with antidepressants compared with placebo
in adults beyond age 24; there was a reduction with antidepressants compared
with placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in
children and adolescents with MDD, obsessive compulsive disorder (OCD), or
other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over
4,400 subjects. The pooled analyses of placebo-controlled
trials in adults with MDD or other psychiatric disorders included a total of
295 short-term trials
(median duration of 2 months) of 11 antidepressant drugs in over 77,000
subjects. There was considerable variation in risk of suicidality among drugs,
but a tendency toward an increase in the younger subjects for almost all drugs studied.
There were differences in absolute risk of suicidality across the different
indications, with the highest incidence in MDD. The risk differences (drug vs.
placebo), however, were relatively stable within age strata and across
indications. These risk differences (drug-placebo difference in the number of
cases of suicidality per 1,000 subjects treated) are provided in Table 1.

Table 1: Risk Differences in the Number of Suicidality
Cases by Age Group in the Pooled Placebo-Controlled Trials of Antidepressants
in Pediatric and Adult Subjects

Age Range

Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Subjects Treated

Increases Compared with Placebo

< 18

14 additional cases

18-24

5 additional cases

Decreases Compared with Placebo

25-64

1 fewer case

≥ 65

6 fewer cases

No suicides occurred in any of the pediatric trials.
There were suicides in the adult trials, but the number was not sufficient to
reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to
longer-term use, i.e., beyond several months. However, there is substantial
evidence from placebo-controlled maintenance trials in adults with depression
that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for
any indication should be monitored appropriately and observed closely for
clinical worsening, suicidality, and unusual changes in behavior, especially
during the initial few months of a course of drug therapy, or at times of dose changes,
either increases or decreases [see BOXED WARNING].

The following symptoms, anxiety, agitation, panic
attacks, insomnia, irritability, hostility, aggressiveness, impulsivity,
akathisia (psychomotor restlessness), hypomania, and mania, have been reported
in adult and pediatric patients being treated with antidepressants for major
depressive disorder as well as for other indications, both psychiatric and
nonpsychiatric. Although a causal link between the emergence of such symptoms
and either the worsening of depression and/or the emergence of suicidal impulses
has not been established, there is concern that such symptoms may represent
precursors to emerging suicidality.

Consideration should be given to changing the therapeutic
regimen, including possibly discontinuing the medication, in patients whose
depression is persistently worse, or who are experiencing emergent suicidality
or symptoms that might be precursors to worsening depression or suicidality,
especially if these symptoms are severe, abrupt in onset, or were not part of
the patient's presenting symptoms.

Families and caregivers of patients being treated with
antidepressants for MDD or other indications , both psychiatric and
nonpsychiatric, should be alerted about the need to monitor patients for the
emergence of agitation, irritability, unusual changes in behavior, and the
other symptoms described above, as well as the emergence of suicidality, and to
report such symptoms immediately to healthcare providers. Such monitoring
should include daily observation by families and caregivers. Prescriptions for
WELLBUTRIN SR should be written for the smallest quantity of tablets cons is
tent with good patient management, in order to reduce the risk of overdose.

WELLBUTRIN SR is not approved for smoking cessation
treatment; however, ZYBAN® is approved for this use. Serious neuropsychiatric
symptoms have been reported in patients taking bupropion for smoking cessation.
These have included changes in mood (including depression and mania),
psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility,
agitation, aggression, anxiety, and panic, as well as suicidal ideation,
suicide attempt, and completed suicide [see BOXED WARNING, ADVERSE
REACTIONS]. Observe patients for the occurrence of neuropsychiatric reactions.
Instruct patients to contact a healthcare professional if such reactions occur.

In many of these cases, a causal relationship to
bupropion treatment is not certain, because depressed mood can be a symptom of
nicotine withdrawal. However, some of the cases occurred in patients taking bupropion
who continued to smoke.

Seizure

WELLBUTRIN SR can cause seizure. The risk of seizure is
dose-related. The dose should not exceed 400 mg per day. Increase the dose
gradually. Discontinue WELLBUTRIN SR and do not restart treatment if the
patient experiences a seizure.

The risk of seizures is also related to patient factors,
clinical situations, and concomitant medications that lower the seizure threshold.
Consider these risks before initiating treatment with WELLBUTRIN SR. WELLBUTRIN
SR is contraindicated in patients with a seizure disorder, current or prior
diagnosis of anorexia nervosa or bulimia, or undergoing abrupt discontinuation
of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see CONTRAINDICATIONS,
DRUG INTERACTIONS]. The following conditions can also increase the risk
of seizure: severe head injury; arteriovenous malformation; CNS tumor or CNS
infection; severe stroke; concomitant use of other medications that lower the
seizure threshold (e.g., other bupropion products, antipsychotics, tricyclic
antidepressants, theophylline, and systemic corticosteroids); metabolic
disorders (e.g., hypoglycemia, hyponatremia, severe hepatic impairment, and
hypoxia); use of illicit drugs (e.g., cocaine); or abuse or misuse of
prescription drugs such as CNS stimulants. Additional predisposing conditions
include diabetes mellitus treated with oral hypoglycemic drugs or insulin; use
of anorectic drugs; and excessive use of alcohol, benzodiazepines, sedative/hypnotics,
or opiates.

Incidence Of Seizure With Bupropion Use

When WELLBUTRIN SR is dosed up to 300 mg per day, the
incidence of seizure is approximately 0.1% (1/1,000) and increases to
approximately 0.4% (4/1,000) at the maximum recommended dose of 400 mg per day.

The risk of seizure can be reduced if the dose of
WELLBUTRIN SR does not exceed 400 mg per day, given as 200 mg twice daily, and
the titration rate is gradual.

Hypertension

Treatment with WELLBUTRIN SR can result in elevated blood
pressure and hypertension. Assess blood pressure before initiating treatment
with WELLBUTRIN SR, and monitor periodically during treatment. The risk of
hypertension is increased if WELLBUTRIN SR is used concomitantly with MAOIs or
other drugs that increase dopaminergic or noradrenergic activity [see CONTRAINDICATIONS].

Data from a comparative trial of the sustained-release
formulation of bupropion HCl, nicotine transdermal system (NTS), the combination
of sustained-release bupropion plus NTS, and placebo as an aid to smoking
cessation suggest a higher incidence of treatment-emergent hypertension in
patients treated with the combination of sustained-release bupropion and NTS. In
this trial, 6.1% of subjects treated with the combination of sustained-release
bupropion and NTS had treatment-emergent
hypertension compared with 2.5%, 1.6%, and 3.1% of subjects treated with
sustained-release bupropion, NTS, and placebo, respectively. The majority of
these subjects had evidence of pre-existing hypertension. Three subjects (1.2%)
treated with the combination of sustained-release bupropion and NTS and 1
subject (0.4%) treated with NTS had study medication discontinued due to hypertension
compared with none of the subjects treated with sustained-release bupropion or
placebo. Monitoring of blood pressure is recommended in patients who receive
the combination of bupropion and nicotine replacement.

In a clinical trial of bupropion immediate-release in MDD
subjects with stable congestive heart failure (N = 36), bupropion was
associated with an exacerbation of pre-existing hypertension in 2 subjects, leading
to discontinuation of bupropion treatment. There are no controlled trials
assessing the safety of bupropion in patients with a recent history of
myocardial infarction or unstable cardiac disease.

Activation Of Mania/Hypomania

Antidepressant treatment can precipitate a manic, mixed,
or hypomanic manic episode. The risk appears to be increased in patients with
bipolar disorder or who have risk factors for bipolar disorder. Prior to initiating
WELLBUTRIN SR, screen patients for a history of bipolar disorder and the
presence of risk factors for bipolar disorder (e.g., family history of bipolar
disorder, suicide, or depression). WELLBUTRIN SR is not approved for use in
treating bipolar depression.

Psychosis And Other Neuropsychiatric Reactions

Depressed patients treated with WELLBUTRIN SR have had a
variety of neuropsychiatric signs and symptoms, including delusions, hallucinations,
psychosis, concentration disturbance, paranoia, and confusion. Some of these
patients had a diagnosis of bipolar disorder. In some cases, these symptoms abated
upon dose reduction and/or withdrawal of treatment. Instruct patients to
contact a healthcare professional if such reactions occur.

Angle-Closure Glaucoma

The pupillary dilation that occurs following use of many
antidepressant drugs including WELLBUTRIN SR may trigger an angle-closure
attack in a patient with anatomically narrow angles who does not have a patentiridectomy.

Hypersensitivity Reactions

Anaphylactoid/anaphylactic reactions have occurred during
clinical trials with bupropion. Reactions have been characterized by pruritus,
urticaria, angioedema, and dyspnea requiring medical treatment. In addition,
there have been rare, spontaneous postmarketing reports of erythema multiforme,
Stevens-Johnson syndrome,
and anaphylactic shock associated with bupropion. Instruct patients to discontinue
WELLBUTRIN SR and consult a healthcare provider if they develop an allergic or anaphylactoid/anaphylactic
reaction (e.g., skin rash, pruritus, hives, chest pain, edema, and shortness of
breath) during treatment.

There are reports of arthralgia, myalgia, fever with rash
and other serum sickness-like symptoms suggestive of delayed hypersensitivity.

Patient Counseling Information

Inform patients, their families, and their caregivers
about the benefits and risks associated with treatment with WELLBUTRIN SR and
counsel them in its appropriate use.

A patient Medication Guide about “Antidepressant
Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts
or Actions,” “Quitting Smoking, Quit-Smoking Medications, Changes in Thinking
and Behavior, Depression, and Suicidal Thoughts or Actions,” and “What Other
Important Information Should I Know About WELLBUTRIN SR?” is available for
WELLBUTRIN SR. Instruct patients, their families, and their caregivers to read
the Medication Guide and assist them in understanding its contents. Patients
should be given the opportunity to discuss the contents of the Medication Guide
and to obtain answers to any questions they may have. The complete text of the Medication
Guide is reprinted at the end of this document.

Advise patients regarding the following issues and to
alert their prescriber if these occur while taking WELLBUTRIN SR.

Suicidal Thoughts And Behaviors

Instruct patients, their families, and/or their
caregivers to be alert to the emergence of anxiety, agitation, panic attacks,
insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor
restlessness), hypomania, mania, other unusual changes in behavior, worsening
of depression, and suicidal ideation, especially early during antidepressant
treatment and when the dose is adjusted up or down. Advise families and
caregivers of patients to observe for the emergence of such symptoms on a day-to-day
basis, since changes may be abrupt. Such symptoms should be reported to the patientâ€™s
prescriber or healthcare professional, especially if they are severe, abrupt in
onset, or were not part of the patientâ€™s presenting symptoms. Symptoms such as
these may be associated with an increased risk for suicidal thinking and
behavior and indicate a need for very close monitoring and possibly changes in
the medication.

Although WELLBUTRIN SR is not indicated for smoking
cessation treatment, it contains the same active ingredient as ZYBAN which is
approved for this use. Advise patients, families and caregivers that quitting
smoking, with or without ZYBAN, may trigger nicotine withdrawal symptoms (e.g.,
including depression or agitation), or worsen pre-existing psychiatric illness.
Some patients have experienced changes in mood (including depression and
mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation,
aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt,
and completed suicide when attempting to quit smoking while taking ZYBAN. If
patients develop agitation, hostility, depressed mood, or changes in thinking
or behavior that are not typical for them, or if patients develop suicidal
ideation or behavior, they should be urged to report these symptoms to their
healthcare provider immediately.

Severe Allergic Reactions

Educate patients on the symptoms of hypersensitivity and
to discontinue WELLBUTRIN SR if they have a severe allergic reaction.

Seizure

Instruct patients to discontinue and not restart
WELLBUTRIN SR if they experience a seizure while on treatment. Advise patients
that the excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic
drugs, or sedatives/hypnotics can increase the risk of seizure. Advise patients
to minimize or avoid use of alcohol.

As the dose is increased during initial titration to
doses above 150 mg per day, instruct patients to take WELLBUTRIN SR in 2
divided doses, preferably with at least 8 hours between successive doses, to minimize
the risk of seizures.

Angle-Closure Glaucoma

Patients should be advised that taking WELLBUTRIN SR can cause
mild pupillary dilation, which in susceptible individuals, can lead to an
episode of angle-closure glaucoma. Pre-existing glaucoma is almost always
open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be
treated definitively with iridectomy. Open-angle glaucoma is not a risk factor
for angle-closure glaucoma. Patients may wish to be examined to determine
whether they are susceptible to angle closure, and have a prophylactic
procedure (e.g., iridectomy), if they are susceptible [see WARNINGS AND
PRECAUTIONS].

Bupropion-Containing Products

Educate patients that WELLBUTRIN SR contains the same
active ingredient (bupropion hydrochloride) found in ZYBAN, which is used as an
aid to smoking cessation treatment, and that WELLBUTRIN SR should not be used
in combination with ZYBAN or any other medications that contain bupropion (such
as WELLBUTRIN®,
the immediate-release formulation and WELLBUTRIN XL ® or FORFIVO XL®, the extended-release
formulations, and APLENZIN®,
the extended-release formulation of bupropion hydrobromide). In addition, there
are a number of generic bupropion HCl products for the immediate-, sustained-,
and extended-release formulations.

Potential For Cognitive And Motor Impairment

Advise patients that any CNS-active drug like WELLBUTRIN SR may impair their
ability to perform tasks requiring judgment or motor and cognitive skills.
Advise patients that until they are reasonably certain that WELLBUTRIN SR does
not adversely affect their performance, they should refrain from driving an
automobile or operating complex, hazardous machinery. WELLBUTRIN SR may lead to
decreased alcohol tolerance.

Concomitant Medications

Counsel patients to notify their healthcare provider if
they are taking or plan to take any prescription or over-the-counter
drugs because WELLBUTRIN SR sustained-release tablets and other drugs may affect
each othersâ€™ metabolisms.

Pregnancy

Advise patients to notify their healthcare provider if
they become pregnant or intend to become pregnant during therapy.

Precautions For Nursing Mothers

Advise patients that WELLBUTRIN SR is present in human
milk in small amounts.

Storage Information

Instruct patients to store WELLBUTRIN SR at room
temperature, between 59°F and 86°F (15°C to 30°C) and keep the tablets dry and
out of the light.

Administration Information

Instruct patients to swallow WELLBUTRIN SR tablets whole
so that the release rate is not altered. Do not chew, divide, or crush tablets;
they are designed to slowly release drug in the body. When patients take more
than 150 mg per day, instruct them to take WELLBUTRIN SR in 2 doses at least 8
hours apart, to minimize the risk of seizures. Instruct patients if they miss a
dose, not to take an extra tablet to make up for the missed dose and to take
the next tablet at the regular time because of the dose-related risk of seizure.
Instruct patients that WELLBUTRIN SR tablets may have an odor. WELLBUTRIN SR
can be taken with or without food.

WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, and ZYBAN are
registered trademarks of the GSK group of companies. The other brands listed
are trademarks of their respective owners and are not trademarks of the GSK
group of companies. The makers of these brands are not affiliated with and do
not endorse the GSK group of companies or its products.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Lifetime carcinogenicity studies were performed in rats
and mice at bupropion doses up to 300 and 150 mg per kg per day, respectively.
These doses are approximately 7 and 2 times the MRHD, respectively, on a mg per
m² basis. In the rat study there was an increase in nodularproliferative
lesions of the liver at doses of 100 to 300 mg per kg per day (approximately 2
to 7 times the MRHD on a mg per m² basis); lower doses were not tested. The
question of whether or not such lesions may be precursors of neoplasms of the
liver is currently unresolved. Similar liver lesions were not seen in the mouse
study, and no increase in malignant tumors of the liver and other organs was
seen in either study.

Bupropion produced a positive response (2 to 3 times
control mutation rate) in 2 of 5 strains in the Ames bacterial mutagenicity
assay. Bupropion produced an increase in chromosomal aberrations in 1 of 3 in vivo
rat bone marrow cytogenetic studies.

A fertility study in rats at doses up to 300 mg per kg
per day revealed no evidence of impaired fertility.

Use In Specific Populations

Pregnancy

Pregnancy Category C

Risk Summary

Data from epidemiological studies of pregnant women
exposed to bupropion in the first trimester indicate no increased risk of
congenital malformations overall. All pregnancies, regardless of drug exposure,
have a background rate of 2% to 4% for major malformations, and 15% to 20% for
pregnancy loss. No clear evidence of teratogenic activity was found in reproductive
developmental studies conducted in rats and rabbits; however, in rabbits,
slightly increased incidences of fetal malformations and skeletal variations
were observed at doses approximately equal to the maximum recommended human
dose (MRHD) and greater and decreased fetal weights were seen at doses twice
the MRHD and greater. WELLBUTRIN SR should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.

Clinical Considerations

Consider the risks of untreated depression when
discontinuing or changing treatment with antidepressant medications during
pregnancy and postpartum.

Human Data

Data from the international bupropion Pregnancy Registry
(675 first trimester exposures) and a retrospectivecohort study using the
United Healthcare database (1,213 first trimester exposures) did not show an
increased risk for malformations overall.

No increased risk for cardiovascular malformations
overall has been observed after bupropion exposure during the first trimester.
The prospectively observed rate of cardiovascular malformations in pregnancies
with exposure to bupropion in the first trimester from the international
Pregnancy Registry was 1.3% (9 cardiovascular malformations/675 first-trimester
maternal bupropion exposures), which is similar to the background rate of
cardiovascular malformations (approximately 1%). Data from the United
Healthcare database and a case-control study (6,853 infants with cardiovascular
malformations and 5,763 with non-cardiovascular malformations) from the
National Birth Defects Prevention Study (NBDPS) did not show an increased risk
for cardiovascular malformations overall after bupropion exposure during the
first trimester.

Study findings on bupropion exposure during the first
trimester and risk for left ventricular outflow tract obstruction (LVOTO) are
inconsistent and do not allow conclusions regarding a possible association. The
United Healthcare database lacked sufficient power to evaluate this
association; the NBDPS found increased risk for LVOTO (n = 10; adjusted OR =
2.6; 95% CI: 1.2, 5.7), and the Slone Epidemiology case control study did not
find increased risk for LVOTO.

Study findings on bupropion exposure during the first
trimester and risk for ventricular septal defect (VSD) are inconsistent and do
not allow conclusions regarding a possible association. The Slone Epidemiology
Study found an increased risk for VSD following first trimester maternal
bupropion exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5.0) but did not find
increased risk for any other cardiovascular malformations studied (including
LVOTO as above). The NBDPS and United Healthcare database study did not find an
association between first trimester maternal bupropion exposure and VSD.

For the findings of LVOTO and VSD, the studies were
limited by the small number of exposed cases, inconsistent findings among
studies, and the potential for chance findings from multiple comparisons in case
control studies.

Animal Data

In studies conducted in rats and rabbits, bupropion was
administered orally during the period of organogenesis at doses of up to 450
and 150 mg per kg per day, respectively (approximately 11 and 7 times the MRHD,
respectively, on a mg per m² basis). No clear evidence of teratogenic 2
activity was found in either species; however, in rabbits, slightly increased
incidences of fetal malformations and skeletal variations were observed at the
lowest dose tested (25 mg per kg per day, approximately equal to the MRHD on a
mg per m² basis) and greater. Decreased fetal weights were observed at 50 mg
per kg and greater.

When rats were administered bupropion at oral doses of up
to 300 mg per kg per day (approximately 7 times the MRHD on a mg per m basis)
prior to mating and throughout pregnancy and lactation, there were no apparent
adverse effects on offspring development.

Nursing Mothers

Bupropion and its metabolites are present in human milk.
In a lactation study of 10 women, levels of orally dosed bupropion and its active
metabolites were measured in expressed milk. The average daily infant exposure
(assuming 150 mL per kg daily consumption) to bupropion and its active
metabolites was 2% of the maternal weight-adjusted dose. Exercise caution when
WELLBUTRIN SR is administered to a nursing woman.

Pediatric Use

Safety and effectiveness in the pediatric population have
not been established [seeBOXED WARNING, WARNINGS AND PRECAUTIONS].

Geriatric Use

Of the approximately 6,000 subjects who participated in
clinical trials with bupropion sustained-release tablets (depression and
smoking cessation trials), 275 were aged ≥ 65 years and 47 were aged
≥ 75 years. In addition, several hundred subjects aged ≥ 65 years
participated in clinical trials using the immediaterelease formulation of
bupropion (depression trials). No overall differences in safety or
effectiveness were observed between these subjects and younger subjects. Reported
clinical experience has not identified differences in responses between the
elderly and younger patients, but greater sensitivity of some older individuals
cannot be ruled out.

Bupropion is extensively metabolized in the liver to
active metabolites, which are further metabolized and excreted by the kidneys.
The risk of adverse reactions may be greater in patients with impaired renal function.
Because elderly patients are more likely to have decreased renal function, it
may be necessary to consider this factor in dose selection; it may be useful to
monitor renal function [see DOSAGE AND ADMINISTRATION, Use in
Specific Populations, CLINICAL PHARMACOLOGY].

Renal Impairment

Consider a reduced dose and/or dosing frequency of
WELLBUTRIN SR in patients with renal impairment (Glomerular Filtration Rate:
less than 90 mL per min). Bupropion and its metabolites are cleared renally and
may accumulate in such patients to a greater extent than usual. Monitor closely
for adverse reactions that could indicate high bupropion or metabolite
exposures [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

Hepatic Impairment

In patients with moderate to severe hepatic impairment
(Child-Pugh score: 7 to 15), the maximum dose of WELLBUTRIN SR is 100 mg per
day or 150 mg every other day. In patients with mild hepatic impairment
(Child-Pugh score: 5 to 6), consider reducing the dose and/or frequency of
dosing [see DOSAGE AND ADMINISTRATION, CLINICAL PHARMACOLOGY].

Overdosage

OVERDOSE

Human Overdose Experience

Overdoses of up to 30 grams or more of bupropion have
been reported. Seizure was reported in approximately one-third of all cases.
Other serious reactions reported with overdoses of bupropion alone included
hallucinations, loss of consciousness, sinus tachycardia, and ECG changes such
as conduction disturbances (including QRS prolongation) or arrhythmias. Fever,
muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory
failure have been reported mainly when bupropion was part of multiple drug
overdoses.

Although most patients recovered without sequelae, deaths
associated with overdoses of bupropion alone have been reported in patients
ingesting large doses of the drug. Multiple uncontrolled seizures, bradycardia,
cardiac failure, and cardiac arrest prior to death were reported in these
patients.

Overdosage Management

Consult a Certified Poison Control Center for up-to-date
guidance and advice. Telephone numbers for certified poison control centers are
listed in the Physician's Desk Reference (PDR). Call 1-800-222- 1222 or refer
to www.poison.org.

There are no known antidotes for bupropion. In case of an
overdose, provide supportive care, including close medical supervision and
monitoring. Consider the possibility of multiple drug overdose. Ensure an
adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital
signs. Induction of emesis is not recommended.

Contraindications

CONTRAINDICATIONS

WELLBUTRIN SR is contraindicated in patients with a
current or prior diagnosis of bulimia oranorexia nervosa as a higher incidence
of seizures was observed in such patients treated with the immediate-release formulation of
bupropion [see WARNINGS AND PRECAUTIONS].

The use of MAOIs (intended to treat psychiatric
disorders) concomitantly with WELLBUTRIN SR or within 14 days of discontinuing
treatment with WELLBUTRIN SR is contraindicated. There is an increased risk of
hypertensive reactions when WELLBUTRIN SR is used concomitantly with MAOIs. The
use of WELLBUTRIN SR within 14 days of discontinuing treatment with an MAOI is
also contraindicated. Starting WELLBUTRIN SR in a patient treated with
reversible MAOIs such as linezolid or intravenous methylene blue is
contraindicated [see DOSAGE AND ADMINISTRATION, WARNINGS AND
PRECAUTIONS, DRUG INTERACTIONS].

WELLBUTRIN SR is contraindicated in patients with known
hypersensitivity to bupropion or other ingredients of WELLBUTRIN SR.
Anaphylactoid/anaphylactic reactions and Stevens- Johnson syndrome have been
reported [see WARNINGS AND PRECAUTIONS].

Clinical Pharmacology

CLINICAL PHARMACOLOGY

Mechanism Of Action

The exact mechanism of the antidepressant action of
bupropion is not known, but is presumed to be related to noradrenergic and/or
dopaminergic mechanisms. Bupropion is a relatively weak inhibitor of the
neuronal reuptake of norepinephrine and dopamine, and does not inhibit the
reuptake of serotonin. Bupropion does not inhibit monoamine oxidase.

Pharmacokinetics

Bupropion is a racemic mixture. The pharmacological
activity and pharmacokinetics of the individual enantiomers have not been
studied. The mean elimination half-life
(±SD) of bupropion after chronic dosing is 21 (±9) hours, and steady-state
plasma concentrations of bupropion are reached within 8 days.

Absorption

The absolute bioavailability of WELLBUTRIN SR in humans
has not been determined because an intravenous formulation for human use is not
available. However, it appears likely that only a small proportion of any
orally administered dose reaches the systemic circulation intact. In rat and
dog studies, the bioavailability of bupropion ranged from 5% to 20%. In humans,
following oral administration of WELLBUTRIN SR, peak plasma concentration (Cmax)
of bupropion is usually achieved within 3 hours.

In a trial comparing chronic dosing with WELLBUTRIN SR
150 mg twice daily to bupropion immediate-release
formulation 100 mg 3 times daily, the steady state Cmax for bupropion after WELLBUTRIN
SR administration was approximately 85% of those achieved after bupropion immediate-release
formulation administration. Exposure (AUC) to bupropion was equivalent for both
formulations. Bioequivalence was also demonstrated for all three major active
metabolites (i.e., hydroxybupropion, threohydrobupropion and
erythrohydrobupropion) for both Cmax and AUC. Thus, at steady state, WELLBUTRIN
SR given twice daily, and the immediate-release
formulation of bupropion given 3 times daily, are essentially bioequivalent for
both bupropion and the 3 quantitatively important metabolites.

WELLBUTRIN SR can be taken with or without food.
Bupropion Cmax and AUC were increased by 11% to 35% and 16% to 19%,
respectively, when WELLBUTRIN SR was administered with food to healthy
volunteers in three trials. The food effect is not considered clinically
significant.

Distribution

In vitro tests show that bupropion is 84% bound to human
plasma proteins at concentrations up to 200 mcg per mL. The extent of protein
binding of the hydroxybupropion metabolite is similar to that for bupropion;
whereas, the extent of protein binding of the threohydrobupropion metabolite is
about half that seen with bupropion.

Metabolism

Bupropion is extensively metabolized in humans. Three
metabolites are active: hydroxybupropion, which is formed via hydroxylation of
the tert-butyl group of
bupropion, and the amino-alcohol
isomers, threohydrobupropion and erythrohydrobupropion, which are formed via
reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal
isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450
enzymes are not involved in the formation of threohydrobupropion. Oxidation of
the bupropion side chain results in the formation of a glycine conjugate of
meta-chlorobenzoic acid,
which is then excreted as the major urinary metabolite. The potency and
toxicity of the metabolites relative to bupropion have not been fully
characterized. However, it has been demonstrated in an antidepressant screening
test in mice that hydroxybupropion is one-half as potent as bupropion, while
threohydrobupropion and erythrohydrobupropion are 5-fold less potent than
bupropion. This may be of clinical importance because the plasma concentrations
of the metabolites are as high as or higher than those of bupropion.

Following a single-dose administration of WELLBUTRIN SR
in humans, Cmax of hydroxybupropion occurs approximately 6 hours post-dose and is approximately 10
times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is
approximately 20 (±5) hours and its AUC at steady state is about 17 times that
of bupropion. The times to peak concentrations for the erythrohydrobupropion
and threohydrobupropion metabolites are similar to that of the hydroxybupropion
metabolite. However, their elimination half-lives
are longer, 33 (±10) and 37 (±13) hours, respectively, and steady-state AUCs are 1.5 and 7 times
that of bupropion, respectively.

Bupropion and its metabolites exhibit linear kinetics
following chronic administration of 300 to 450 mg per day.

Elimination

Following oral administration of 200 mg of 14C-bupropion in humans, 87% and
10% of the radioactive dose were recovered in the urine and feces,
respectively. Only 0.5% of the oral dose was excreted as unchanged bupropion.

Population Subgroups

Factors or conditions altering metabolic capacity (e.g.,
liver disease, congestive heart failure [CHF], age, concomitant medications,
etc.) or elimination may be expected to influence the degree and extent of accumulation
of the active metabolites of bupropion. The elimination of the major
metabolites of bupropion may be affected by reduced renal or hepatic function
because they are moderately polar compounds and are likely to undergo further
metabolism or conjugation in the liver prior to urinary excretion.

Renal Impairment: There is limited information on
the pharmacokinetics of bupropion in patients with renal impairment. An
inter-trial comparison between normal subjects and subjects with end-stage
renal failure demonstrated that the parent drug Cmax and AUC values were
comparable in the 2 groups, whereas the hydroxybupropion and
threohydrobupropion metabolites had a 2.3- and 2.8-fold increase, respectively,
in AUC for subjects with end-stage renal failure. A second trial, comparing
normal subjects and subjects with moderate-to-severe renal impairment (GFR 30.9
± 10.8 mL per min), showed that after a single 150-mg dose of sustained-release
bupropion, exposure to bupropion was approximately 2-fold higher in subjects
with impaired renal function, while levels of the hydroxybupropion and
threo/erythrohydrobupropion (combined) metabolites were similar in the 2 groups.
Bupropion is extensively metabolized in the liver to active metabolites, which
are further metabolized and subsequently excreted by the kidneys. The elimination
of the major metabolites of bupropion may be reduced by impaired renal
function. WELLBUTRIN SR should be used with caution in patients with renal
impairment and a reduced frequency and/or dose should be considered [see Use
in Specific Populations].

Hepatic Impairment: The effect of hepatic
impairment on the pharmacokinetics of bupropion was characterized in 2
single-dose trials, one in subjects with alcoholic liver disease and one in
subjects with mild-to-severe cirrhosis. The first trial demonstrated that the
half-life of
hydroxybupropion was significantly longer in 8 subjects with alcoholic liver
disease than in 8 healthy volunteers (32 ± 14 hours versus 21 ± 5 hours,
respectively). Although not statistically significant, the AUCs for bupropion
and hydroxybupropion were more variable and tended to be greater (by 53% to
57%) in volunteers with alcoholic liver disease. The differences in half-life for bupropion and the
other metabolites in the 2 groups were minimal.

The second trial demonstrated no statistically
significant differences in the pharmacokinetics of bupropion and its active
metabolites in 9 subjects with mild-to-moderate hepatic cirrhosis compared with
8 healthy volunteers. However, more variability was observed in some of the
pharmacokinetic parameters for bupropion (AUC, Cmax, and Tmax) and its active
metabolites (t½) in subjects with mildto- moderate hepatic cirrhosis. In
subjects with severe hepatic cirrhosis, significant alterations in the pharmacokinetics
of bupropion and its metabolites were seen (Table 5).

Left Ventricular Dysfunction: During a chronic
dosing trial with bupropion in 14 depressed subjects with left ventricular
dysfunction (history of CHF or an enlarged heart on x-ray), there was no
apparent effect on the pharmacokinetics of bupropion or its metabolites,
compared with healthy volunteers.

Age: The effects of age on the pharmacokinetics of
bupropion and its metabolites have not been fully characterized, but an
exploration of steady-state
bupropion concentrations from several depression efficacy trials involving
subjects dosed in a range of 300 to 750 mg per day, on a 3-times-daily schedule,
revealed no relationship between age (18 to 83 years) and plasma concentration
of bupropion. A single-dose
pharmacokinetic trial demonstrated that the disposition of bupropion and its
metabolites in elderly subjects was similar to that of younger subjects. These
data suggest there is no prominent effect of age on bupropion concentration;
however, another single- and multiple-dose pharmacokinetics trial suggested
that the elderly are at increased risk for accumulation of bupropion and its
metabolites [see Use in Specific Populations].

Gender: Pooled analysis of bupropion
pharmacokinetic data from 90 healthy male and 90 healthy female volunteers
revealed no sex-related
differences in the peak plasma concentrations of bupropion. The mean systemic
exposure (AUC) was approximately 13% higher in male volunteers compared with female
volunteers. The clinical significance of this finding is unknown.

Smokers: The effects of cigarettesmoking on the
pharmacokinetics of bupropion were studied in 34 healthy male and female
volunteers; 17 were chronic cigarette smokers and 17 were nonsmokers. Following
oral administration of a single 150-mg
dose of bupropion, there were no statistically significant differences in Cmax,
half-life, Tmax, AUC, or clearance of bupropion or its active metabolites
between smokers and nonsmokers.

Drug Interactions

Potential for Other Drugs to Affect WELLBUTRIN SR:In vitro studies indicate that bupropion is primarily metabolized to
hydroxybupropion by CYP2B6. Therefore, the potential exists for drug
interactions between WELLBUTRIN SR and drugs that are inhibitors or inducers of
CYP2B6. In addition, in vitro studies suggest that paroxetine, sertraline,
norfluoxetine, fluvoxamine, and nelfinavir inhibit the hydroxylation of
bupropion.

Inhibitors of CYP2B6: Ticlopidine, Clopidogrel: In
a trial in healthy male volunteers, clopidogrel 75 mg once daily or ticlopidine
250 mg twice daily increased exposures (Cmax and AUC) of bupropion by 40% and
60% for clopidogrel, and by 38% and 85% for ticlopidine, respectively. The
exposures (Cmax and AUC) of hydroxybupropion were decreased 50% and 52%,
respectively, by clopidogrel, and 78% and 84%, respectively, by ticlopidine. This
effect is thought to be due to the inhibition of the CYP2B6-catalyzed bupropion
hydroxylation.

Prasugrel:Prasugrel is a weak inhibitor of
CYP2B6. In healthy subjects, prasugrel increased bupropion Cmax and AUC values
by 14% and 18%, respectively, and decreased Cmax and AUC values of hydroxybupropion,
an active metabolite of bupropion, by 32% and 24%, respectively.

Cimetidine: The threohydrobupropion metabolite of
bupropion does not appear to be produced by cytochrome P450 enzymes. The
effects of concomitant administration of cimetidine on the pharmacokinetics of
bupropion and its active metabolites were studied in 24 healthy young male volunteers.
Following oral administration of bupropion 300 mg with and without cimetidine
800 mg, the pharmacokinetics of bupropion and hydroxybupropion were unaffected.
However, there were 16% and 32% increases in the AUC and Cmax, respectively, of
the combined moieties of threohydrobupropion and erythrohydrobupropion.

Citalopram:Citalopram did not affect the
pharmacokinetics of bupropion and its three metabolites.

Inducers of CYP2B6:Ritonavir and Lopinavir: In a
healthy volunteer trial, ritonavir 100 mg twice daily reduced the AUC and Cmax
of bupropion by 22% and 21%, respectively. The exposure of the hydroxybupropion
metabolite was decreased by 23%, the threohydrobupropion decreased by 38%, and the
erythrohydrobupropion decreased by 48%.

In a second healthy volunteer trial, ritonavir at a dose
of 600 mg twice daily decreased the AUC and the Cmax of bupropion by 66% and 62%,
respectively. The exposure of the hydroxybupropion metabolite was decreased by
78%, the threohydrobupropion decreased by 50%, and the erythrohydrobupropion decreased
by 68%.

In another healthy volunteer trial, lopinavir 400
mg/ritonavir 100 mg twice daily decreased bupropion AUC and Cmax by 57%. The
AUC and Cmax of hydroxybupropion were decreased by 50% and 31%, respectively.

Efavirenz: In a trial in healthy volunteers,
efavirenz 600 mg once daily for 2 weeks reduced the AUC and Cmax of bupropion
by approximately 55% and 34%, respectively. The AUC of hydroxybupropion was
unchanged, whereas Cmax of hydroxybupropion was increased by 50%.

Carbamazepine, Phenobarbital, Phenytoin: While not
systematically studied, these drugs may induce the metabolism of bupropion.

Potential For WELLBUTRIN SR To Affect Other Drugs

Animal data indicated that bupropion may be an inducer of
drug-metabolizing enzymes in humans. In one trial, following chronic
administration of bupropion 100 mg three times daily to 8 healthy male volunteers
for 14 days, there was no evidence of induction of its own metabolism.
Nevertheless, there may be potential for clinically important alterations of
blood levels of co-administered drugs.

Drugs Metabolized by CYP2D6:In vitro, bupropion
and its metabolites (erythrohydrobupropion, threohydrobupropion,
hydroxybupropion) are CYP2D6 inhibitors. In a clinical trial of 15 male
subjects (ages 19 to 35 years) who were extensive metabolizers of CYP2D6,
bupropion 300 mg per day followed by a single dose of 50 mg desipramine
increased the Cmax, AUC, and t½ of desipramine by an average of approximately
2-, 5-, and 2-fold, respectively. The effect was present for at least 7 days after
the last dose of bupropion. Concomitant use of bupropion with other drugs metabolized
by CYP2D6 has not been formally studied.

Citalopram: Although citalopram is not primarily
metabolized by CYP2D6, in one trial bupropion increased the Cmax and AUC of
citalopram by 30% and 40%, respectively.

Lamotrigine: Multiple oral doses of bupropion had
no statistically significant effects on the single-dose pharmacokinetics of
lamotrigine in 12 healthy volunteers.

Clinical Studies

The efficacy of the immediate-release formulation of bupropion in the treatment
of major depressive disorder was established in two 4-week, placebo-controlled
trials in adult inpatients with MDD (Trials 1 and 2 in Table 6) and in one 6-week, placebo-controlled trial in adult
outpatients with MDD (Trial 3 in Table 6). In the first trial, the dose range
of bupropion was 300 mg to 600 mg per day administered in divided doses; 78% of
subjects were treated with doses of 300 mg to 450 mg per day. This trial demonstrated
the effectiveness of the immediate-release
formulation of bupropion by the Hamilton Depression Rating Scale (HDRS) total
score, the HDRS depressed mood item (Item 1), and the Clinical Global
Impressions severity score (CGI-S). The second trial included 2 doses of the
immediate-release formulation
of bupropion (300 and 450 mg per day) and placebo. This trial demonstrated the effectiveness
of the immediate-release
formulation of bupropion, but only at the 450-mg-per-day
dose. The efficacy results were significant for the HDRS total score and the
CGI-S score, but not for HDRS Item 1. In the third trial, outpatients were
treated with 300 mg per day of the immediate-release
formulation of bupropion. This trial demonstrated the efficacy of the immediate-release formulation of bupropion
as measured by the HDRS total score, the HDRS Item 1, the Montgomery-Asberg Depression Rating Scale
(MADRS), the CGI-S score, and the CGI-Improvement Scale (CGI-I) score.

Table 6: Efficacy of Immediate-Release Bupropion for
the Treatment of Major Depressive Disorder

Trial Number

Treatment Group

Primary Efficacy Measure: HDRS

Mean Baseline Score (SD)

LS Mean Score at Endpoint Visit (SE)

Placebo-subtracted Differencea (95% CI)

Trial 1

Immediate-Release Bupropion 300-600 mg/dayb (n = 48)

28.5 (5.1)

14.9 (1.3)

-4.7 (-8.8, -0.6)

Placebo (n = 27)

29.3 (7.0)

19.6 (1.6)

--

Mean Baseline Score (SD)

LS Mean Change from Baseline (SE)

Placebo-subtracted Differencea (95% CI)

T rial 2

Immediate-Release Bupropion 300 mg/day (n = 36)

32.4 (5.9)

-15.5 (1.7)

-4.1

Immediate-Release Bupropion 450 mg/dayb (n = 34)

34.8 (4.6)

-17.4 (1.7)

-5.9 (-10.5, -1.4)

Placebo (n = 39)

32.9 (5.4)

-11.5 (1.6)

--

T rial 3

Immediate-Release Bupropion 300 mg/dayb (n= 110)

26.5 (4.3)

-12.0 (NA)

-3.9 (-5.7, -1.0)

Placebo (n = 106)

27.0 (3.5)

-8.7 (NA)

--

n: sample size; SD: standard deviation; SE: standard
error; LS Mean: least-squares mean; CI: unadjusted confidence interval included
for doses that were demonstrated to be effective; NA: not available.aDifference (drug minus placebo) in least-squares estimates with respect
to the primary efficacy parameter. For Trial 1, it refers to the mean score at
the endpoint visit; for Trials 2 and 3, it refers to the mean change from baseline
to the endpoint visit.bDoses that are demonstrated to be statistically significantly
superior to placebo.

Although there are not as yet independent trials
demonstrating the antidepressant effectiveness of the sustained-release formulation of
bupropion, trials have demonstrated the bioequivalence of the immediate-release and sustained-release forms of bupropion
under steady-state
conditions, i.e., bupropion sustained-release
150 mg twice daily was shown to be bioequivalent to 100 mg 3 times daily of the
immediate-release
formulation of bupropion, with regard to both rate and extent of absorption, for
parent drug and metabolites.

In a longer-term trial, outpatients meeting DSM-IV
criteria for major depressive disorder, recurrent type, who had responded
during an 8-week open trial on WELLBUTRIN SR (150 mg twice daily) were randomized
to continuation of their same dose of WELLBUTRIN SR or placebo for up to 44
weeks of observation for relapse. Response during the open phase was defined as
CGI Improvement score of 1 (very much improved) or 2 (much improved) for each
of the final 3 weeks. Relapse during the doubleblind phase was defined as the
investigator's judgment that drug treatment was needed for worsening depressive
symptoms. Patients receiving continued treatment with WELLBUTRIN SR experienced
significantly lower relapse rates over the subsequent 44 weeks compared with
those receiving placebo.

Medication Guide

PATIENT INFORMATION

Read this Medication Guide carefully before you start
taking WELLBUTRIN SR and each time you get a refill. There may be new
information. This information does not take the place of talking with your healthcare
provider about your medical condition or your treatment. If you have any
questions about WELLBUTRIN SR, ask your healthcare provider or pharmacist.

IMPORTANT: Be sure to read the three sections of this
Medication Guide. The first section is about the risk of suicidal thoughts and
actions with antidepressant medicines; the second section is about the risk of
changes in thinking and behavior, depression and suicidal thoughts or actions with
medicines used to quit smoking; and the third section is entitled “What Other
Important Information Should I Know About WELLBUTRIN SR?”

Antidepressant Medicines, Depression and Other Serious
Mental Illnesses, and Suicidal Thoughts or Actions

This section of the Medication Guide is only about the
risk of suicidal thoughts and actions with antidepressant medicines. Talk to
your healthcare provider or your family member’s healthcare provider about:

Never stop an antidepressant medicine without first
talking to a healthcare provider. Stopping an antidepressant medicine
suddenly can cause other symptoms.

Antidepressants are medicines used to treat depression
and other illnesses. It is important to discuss all the risks of treating
depression and also the risks of not treating it. Patients and their families
or other caregivers should discuss all treatment choices with the healthcare provider,
not just the use of antidepressants.

Antidepressant medicines have other side effects. Talk to the healthcare provider about the side effects of the medicine
prescribed for you or your family member.

Antidepressant medicines can interact with other
medicines. Know all of the medicines that you or your family member takes.
Keep a list of all medicines to show the healthcare provider. Do not start new
medicines without first checking with your healthcare provider.

It is not known if WELLBUTRIN SR is safe and effective in
children under the age of 18.

This section of the Medication Guide is only about the
risk of changes in thinking and behavior, depression and suicidal thoughts or
actions with drugs used to quit smoking.

Although WELLBUTRIN SR is not a treatment for quitting
smoking, it contains the same active ingredient (bupropion hydrochloride) as
ZYBAN which is used to help patients quit smoking.

Some people have had changes in behavior, hostility,
agitation, depression, suicidal thoughts or actions while taking bupropion to
help them quit smoking. These symptoms can develop during treatment with bupropion
or after stopping treatment with bupropion.

If you, your family member, or your caregiver notice
agitation, hostility, depression, or changes in thinking or behavior that are
not typical for you, or you have any of the following symptoms, stop taking bupropion
and call your healthcare provider right away:

thoughts about suicide or dying

attempts to commit suicide

new or worse depression

new or worse anxiety

panic attacks

feeling very agitated or restless

acting aggressive, being angry, or violent

acting on dangerous impulses

an extreme increase in activity and talking (mania)

abnormal thoughts or sensations

seeing or hearing things that are not there (hallucinations)

feeling people are against you (paranoia)

feeling confused

other unusual changes in behavior or mood

When you try to quit smoking, with or without bupropion,
you may have symptoms that may be due to nicotine withdrawal, including urge to
smoke, depressed mood, trouble sleeping, irritability, frustration, anger,
feeling anxious, difficulty concentrating, restlessness, decreased heart rate,
and increased appetite or weight gain. Some people have even experienced
suicidal thoughts when trying to quit smoking without medication. Sometimes
quitting smoking can lead to worsening of mental health problems that you
already have, such as depression.

Before taking bupropion, tell your healthcare provider if
you have ever had depression or other mental illnesses. You should also tell
your healthcare provider about any symptoms you had during other times you
tried to quit smoking, with or without bupropion.

What Other Important Information Should I Know About
WELLBUTRIN SR?

Seizures : There is a chance of having a seizure
(convulsion, fit) with WELLBUTRIN SR, especially in people:

with certain medical problems.

who take certain medicines.

The chance of having seizures increases with higher doses
of WELLBUTRIN SR. For more information, see the sections “Who should not take
WELLBUTRIN SR?” and “What should I tell my healthcare provider before taking
WELLBUTRIN SR?” Tell your healthcare provider about all of your medical
conditions and all the medicines you take. Do not take any other medicines
while you are taking WELLBUTRIN SR unless your healthcare provider has said it
is okay to take them.

If you have a seizure while taking WELLBUTRIN SR, stop
taking the tablets and call your healthcare provider right away. Do not
take WELLBUTRIN SR again if you have a seizure.

High blood pressure (hypertension). Some people get
high blood pressure, that can be severe, while taking WELLBUTRIN SR. The
chance of high blood pressure may be higher if you also use nicotine
replacement therapy (such as a nicotine patch) to help you stop smoking.

Manic episodes. Some people may have periods of mania
while taking WELLBUTRIN SR, including:

Greatly increased energy

Severe trouble sleeping

Racing thoughts

Reckless behavior

Unusually grand ideas

Excessive happiness or irritability

Talking more or faster than usual
If you have any of the above symptoms of mania, call your healthcare provider.

Unusual thoughts or behaviors. Some patients have
unusual thoughts or behaviors while taking WELLBUTRIN, including delusions
(believe you are someone else), hallucinations (seeing or hearing things that
are not there), paranoia (feeling that people are against you), or feeling confused.
If this happens to you, call your healthcare provider.

Visual problems.

eye pain

changes in vision

swelling or redness in or around the eye
Only some people are at risk for these problems. You may want to undergo an eye
examination to see if you are at risk and receive preventative treatment if you
are.

Severe allergic reactions. Some people can have severe
allergic reactions to WELLBUTRIN SR. Stop taking WELLBUTRIN SR and call your
healthcare provider right away if you get a rash, itching, hives, fever,
swollen lymph glands, painful sores in the mouth or around the eyes, swelling
of the lips or tongue, chest pain, or have trouble breathing. These could be
signs of a serious allergic reaction.

What is WELLBUTRIN SR?

WELLBUTRIN SR is a prescription medicine used to treat
adults with a certain type of depression called major depressive disorder.

are taking any other medicines that contain bupropion,
ZYBAN (used to help people stop smoking) APLENZIN®, FORFIVO XL®,
WELLBUTRIN®, or WELLBUTRIN XL®. Bupropion is the same active
ingredient that is in WELLBUTRIN SR.

drink a lot of alcohol and abruptly stop drinking, or use
medicines called sedatives (these make you sleepy), benzodiazepines, or
anti-seizure medicines, and you stop using them all of a sudden.

do not take an MAOI within 2 weeks of stopping WELLBUTRIN
SR unless directed to do so by your healthcare provider.

do not start WELLBUTRIN SR if you stopped taking an MAOI
in the last 2 weeks unless directed to do so by your healthcare provider.

are allergic to the active ingredient in WELLBUTRIN SR,
bupropion, or to any of the inactive ingredients. See the end of this
Medication Guide for a complete list of ingredients in WELLBUTRIN SR.

What should I tell my healthcare provider before
taking WELLBUTRIN SR?

Tell your healthcare provider if you have ever had
depression, suicidal thoughts or actions, or other mental health problems. See
“Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and
Suicidal Thoughts or Actions.”

Tell your healthcare provider about your other medical
conditions including if you:

are a diabetic taking insulin or other medicines to
control your blood sugar.

drink alcohol.

abuse prescription medicines or street drugs.

are pregnant or plan to become pregnant.

are breastfeeding. WELLBUTRIN passes into your milk in
small amounts.

Tell your healthcare provider about all the medicines
you take, including prescription, overthe- counter medicines, vitamins, and
herbal supplements. Many medicines increase your chances of having seizures or
other serious side effects if you take them while you are taking WELLBUTRIN SR.

How should I take WELLBUTRIN SR?

Take WELLBUTRIN SR exactly as prescribed by your
healthcare provider.

Swallow WELLBUTRIN SR tablets whole. Do not chew, cut,
or crush WELLBUTRIN SR tablets. If you do, the medicine will be released
into your body too quickly. If this happens you may be more likely to get side
effects including seizures. Tell your healthcare provider if you cannot s
wallow tablets.

Take WELLBUTRIN SR at the same time each day.

Take your doses of WELLBUTRIN SR at least 8 hours apart.

You may take WELLBUTRIN SR with or without food.

If you miss a dose, do not take an extra dose to make up
for the dose you missed. Wait and take your next dose at the regular time. This
is very important. Too much WELLBUTRIN SR can increase your chance of
having a seizure.

If you take too much WELLBUTRIN SR, or overdose, call
your local emergency room or poison control center right away.

Do not take any other medicines while taking
WELLBUTRIN SR unless your healthcare provider has told you it is okay.

If you are taking WELLBUTRIN SR for the treatment of
major depressive disorder, it may take several weeks for you to feel that
WELLBUTRIN SR is working. Once you feel better, it is important to keep taking
WELLBUTRIN SR exactly as directed by your healthcare provider. Call your
healthcare provider if you do not feel WELLBUTRIN SR is working for you.

Limit or avoid using alcohol during treatment with
WELLBUTRIN SR. If you usually drink a lot of alcohol, talk with your healthcare
provider before suddenly stopping. If you suddenly stop drinking alcohol, you
may increase your chance of having seizures.

Do not drive a car or use heavy machinery until you know
how WELLBUTRIN SR affects you. WELLBUTRIN SR can affect your ability to do
these things safely.

What are possible side effects of WELLBUTRIN SR?

See “What Other Important Information Should I Know
About WELLBUTRIN SR?”

If you have nausea, take your medicine with food. If you
have trouble sleeping, do not take your medicine too close to bedtime.

Tell your healthcare provider right away about any side
effects that bother you.

These are not all the possible side effects of WELLBUTRIN
SR. For more information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects.
You may report side effects to FDA at 1-800-FDA-1088.

You may also report side effects to GlaxoSmithKline at
1-888-825-5249.

How should I store WELLBUTRIN SR?

Store WELLBUTRIN SR at room temperature between 59°F and
86°F (15°C to 30°C).

Keep WELLBUTRIN SR dry and out of the light.

WELLBUTRIN SR tablets may have an odor.

Keep WELLBUTRIN SR and all medicines out of the reach
of children.

General Information about WELLBUTRIN SR.

Medicines are sometimes prescribed for purposes other
than those listed in a Medication Guide. Do not use WELLBUTRIN SR for a
condition for which it was not prescribed. Do not give WELLBUTRIN SR to other
people, even if they have the same symptoms you have. It may harm them.

If you take a urine drug screening test, WELLBUTRIN SR
may make the test result positive for amphetamines. If you tell the person
giving you the drug screening test that you are taking WELLBUTRIN SR, they can
do a more specific drug screening test that should not have this problem.

This Medication Guide summarizes important information
about WELLBUTRIN SR. If you would like more information, talk with your
healthcare provider. You can ask your healthcare provider or pharmacist for
information about WELLBUTRIN SR that is written for healthcare professionals.

For more information about WELLBUTRIN SR, go to
www.wellbutrin.com or call 1-888-825-5249.